Homozygous sickle cell disease (HbSS) is a major health problem throughout the United States and the world that results in vaso- occlusive events, a variety of secondary disease complications, and a reduced life expectancy. HbSS is a genetic disorder Characterized by the sickling of red blood cells (RBC) due to the replacement of glutamic acid with valine in position 6 on the beta chains of hemoglobin. As a result of this structural change, the life span of the RBC is greatly reduced from the normal 120 days to approximately 10 days. The sickling of RBCs leads to a chronic anemia and increased RBC catabolism and synthesis. These physiological perturbations have the potential to promote increased energy expenditure, increased protein breakdown and synthesis, increased anaerobic metabolism, and altered insulin action. Each of these metabolic derangements is capable of altering specific substrate oxidation and increasing protein and energy demands. The overall aim of the proposed research is to determine the impact of HbSS on whole-body and skeletal muscle nutrient metabolism and demands. Two separate protocols have been designed to identify the mechanisms by which protein and energy demands are increased during HbSS. These protocols will 1) define how changes in nutrient metabolism during HbSS alter energy metabolism basally and during the simulated ingestion of a meal, 2) determine whether increased protein and/or energy availability improves protein homeostasis in HbSS patients 3) identify how the protein synthetic demands of RBCs and other specific tissues impact upon the protein and energy requirements in HbSS, and 4) define the influence of HbSS on insulin-mediated nutrient utilization. Therefore, the protocols will focus on events associated with post-absorptive, meal-related, and insulin-mediated metabolism. These experiments will use isotopic tracer techniques, indirect calorimetry, nutrient infusions, and euglycemic-hyperinsulinemic clamps in HbSS patients. When combined, the proposed protocols will enhance our understanding of how HbSS alters protein and energy metabolism and will identify mechanisms for these alterations. The contribution of HbSS to health care costs is significant, and the knowledge gained from these studies will enable us to better understand the various metabolic processes associated with HbSS. This knowledge will assist in the design of appropriate nutritional regimens, thereby culminating in better disease outcomes.